Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia
Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia
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DOI：
10.1038/leu.2013.369
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发表时间：
2014-06-01
期刊：
影响因子：
11.4
通讯作者：
Martelli, A. M.
中科院分区：
文献类型：
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作者：
Lonetti, A.;Antunes, I. L.;Martelli, A. M.
组成型活性磷酸肌醇3-激酶（PI 3 K）信号传导是T细胞急性淋巴细胞白血病（T-ALL）的共同特征，其中它上调细胞增殖、存活和耐药性。这些观察结果为PI 3 K抑制剂在T-ALL治疗中的应用提供了令人信服的权重。在这里，我们分析了泛PI 3 K抑制剂NVP-BKM 120（BKM 120）的治疗潜力，这是一种口服生物可利用的2，6-二吗啉代嘧啶衍生物，已进入实体瘤的临床试验，对T-ALL细胞系和患者样本。BKM 120处理导致G（2）/M期细胞周期阻滞和凋亡，对一组T-ALL细胞系和患者T淋巴母细胞具有细胞毒性，并促进Akt和S6 RP的剂量和时间依赖性去磷酸化。即使与模拟骨髓微环境的MS-5基质细胞共培养，BKM 120仍保持其对Jurkat细胞的促凋亡活性。值得注意的是，BKM 120与目前用于治疗T-ALL患者的化疗剂协同作用。此外，在人T-ALL的皮下异种移植模型中体内施用BKM 120显著延迟肿瘤生长，从而延长存活时间。总之，我们的研究结果表明，BKM 120，无论是单独或与化疗药物组合，可能是一种有效的治疗T-ALL，具有异常上调PI 3 K信号通路。
Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G(2)/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose-and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.